Some electrophysiological characteristics of alcoholics [e.g., low P3 amplitude of the Event-Related Potential (ERP)] are already manifested by their high risk (HR) offspring and are considered to be biological markers of a predisposition to develop alcohol use disorders (AUDs). Recently developed time-frequency methods reveal event-related oscillations (EROs) that underlie ERPs, and provide a window into neuronal network functioning, suggesting frontal lobe dysfunction in alcoholics and HR. P3 amplitude has been found to be related to level of impulsivity in alcoholics, and individuals with increased impulsivity manifest reduced activation in frontal areas. Electrophysiological and functional imaging studies of HR individuals strongly implicate impaired frontal lobe functioning and vulnerability in fronto-parietal circuits. The proposed project plans to further evaluate disinhibition and frontal lobe dysfunction in young adult HR offspring of alcoholics by implementing paradigms that assess response activation/inhibition with neurophysiological, neuropsychological and neuroimaging methods. Novel time-frequency methods recently developed in our laboratory and those under development allow the investigation of underlying neural oscillations and their synchrony in several frequency bands (delta, theta, alpha, beta, and gamma) during early and late processing of cognitive tasks. It is hypothesized that HR will utilize similar networks for different aspects of cognitive processing, instead of specialized networks to optimize performance, and that their neural networks may not synchronize effectively. This may be due to ineffective cross-linking of neural assemblies, with structural bases in dendritic loss, impairment in interneuron architecture or long-range communication, as indicated by studies documenting white matter pathologies, thus affecting feedforward and feedback mechanisms across brain regions. To complement electrophysiological studies, structural/functional (fMRI) imaging using the same Go/NoGo and gambling tasks will be implemented to understand the (frontal) circuits and localize network impairments that are associated with response inhibition, error/outcome evaluation and reward processing. To supplement resting EEG coherence findings in alcoholics and HR, Diffusion Tensor Imaging (DTI) will be implemented to examine differences in myelination with respect to coherence. Advanced regression and classification methods will be used to investigate the relationships between electrophysiological measures, structural/functional indices, impulsivity, to identify those that are most important in predicting risk or protection, and to identify subgroups more or less likely to develop AUDs and related disorders. Electrophysiological phenotypes not only provide biological vulnerability markers to identify those at risk, but also provide insight into some causative pathophysiological processes involved in the development of AUD related disorders. Findings from multiple domains will have important implications for cognitive, behavioral and neural liabilities involved in risk and the transition from risk drinking to dependence, with utility in treatment and prevention protocols. PUBLIC HEALTH RELEVANCE: This project will address important challenges of identifying subgroups at risk to develop alcohol use and related disorders through neurophysiological, neuropsychological and neuroimaging approaches. It is of the utmost importance to elucidate the underlying predispositions to develop alcoholism in order to create effective prevention strategies. The findings from this grant will also have important implications for cognitive, behavioral and pharmacological treatment protocols.